Pyrazolylaminobenzimidazole derivatives as jak inhibitors

ABSTRACT

The present invention provides compounds of the formula below (I′): where R, and R1-R3 are as described herein, methods of treating patients for certain types of autoimmune diseases and cancer, and processes for preparing the compounds.

The present invention relates to benzimidazole compounds and theirpharmaceutically acceptable salts, that inhibit Janus kinase 1 (JAK1),pharmaceutical compositions comprising the compounds, methods of usingthe compounds to treat certain types of autoimmune diseases and cancer,and processes for preparing the compounds.

The family of Janus kinases (JAK1, JAK2, JAK3 and TYK2) areintracellular protein tyrosine kinases with essential roles in immunefunction, inflammation, and hematopoiesis through the Januskinase-signal transducer and activator of transcription (the JAK-STAT)pathway. In response to extracellular polypeptides such as type I andtype II cytokines, the Janus kinases regulate the tyrosinephosphorylation of various effectors and initiate activation ofdownstream signaling pathways inducing different physiologicalresponses. Specifically the JAK1 isoform plays a key role in types I andII interferon signaling and elicits signals from the interleukin-2(IL-2), interleukin-4 (IL-4), glycoprotein 130 (gp130) and class IIreceptor families. As such, small molecule inhibition of JAK1 mayintervene in the signaling pathways involved in oncology, inflammationand autoimmune diseases. Ghoreschi K et al. Immunological Review 2009,228, 273-287 and Zak M. et al. Med Chem. 2013, 56, 4764-4785.

Despite the recent successes of JAK inhibitor agents, there is still aneed to discover and develop inhibitors, which selectively target asingle JAK isoform. This can mitigate the risk of off target affects.

Janus kinase inhibitor compounds are known in the literature. Forexample, US 2015/0203455 discloses certain benzimidazole compounds thatare JAK inhibitors and which are touted as being useful to treatautoimmune diseases, inflammatory diseases and proliferative diseasesinter alia.

There remains a need to provide alternative JAK1 inhibitors fortreatment of autoimmune diseases particularly for immunologicaldiseases, such as arthritis, rheumatoid arthritis, and diabeticnephropathy. In addition, there remains a need to provide selective JAK1inhibitors. The present invention provides certain inhibitors of JAK1,which can address one or more of these needs.

The present invention provides a compound of Formula 1, or apharmaceutically acceptable salt thereof:

where R is selected from: H, —C₁₋₃ alkyl, —CH₂CH(OH)CH₃, or —C₂₋₃alkyl-O—CH₃,

R1 is selected from: H, —CH₃ and —OCH₃; R2 is —CHF₂ or —CF₃; and R3 is Hor —CH₃; provided that when R2 is —CF₃ and R3 is H, either R or R1 canbe —CH₃ but not both. The bond illustrated as

indicates the point of attachment of the tetrahydropyran ring orpyridine ring to the rest of the molecule.

The present invention provides a compound of Formula 2, or apharmaceutically acceptable salt there, which is,

where R is selected from: H, —C₁₋₃ alkyl, —CH₂CH(OH)CH₃, or —C₂₋₃alkyl-O—CH₃,

R1 is selected from: H, —CH₃ and —OCH; R2 is —CHF₂ or —CF₃; and R3 is Hor —CH₃; provided that when R2 is —CF₃ and R3 is CH₃, either R or R1 canbe —CH₃ but not both.

In one form, the present invention provides a compound according toFormula 1 or 2 where R is selected from: —CH₃, —CH₂CH₃, and

or a pharmaceutically acceptable salt thereof. In certain embodiments. Ris —CH₃, or —CH₂CH₃. In other embodiments, R is

In another form the present invention provides a compound according toFormula 1 or 2 where R is

where the bond illustrated as

indicates the point of attachment to the rest of the molecule. Inanother form, the present invention provides a compound according toFormula 1 or 2 where R is

In another form, the present invention provides a compound according toFormula 1 or 2 where R1 is selected from: H, —CH₃, and —OCH₃. In certainembodiments R1 is H or —CH₃. In other embodiments, R1 is —OCH₃.

In another form, the present invention provides a compound according toFormula 1 or 2 where R2 is —CF₃. In certain embodiments of this form, Ris —CH₃, or —CH₂CH₃ and R1 is —CH₃, or —OCH₃. In other embodiments ofthis form, R is

and R1 is H.

In another form, the present invention provides a compound according toFormula 1 or 2 wherein R3 is —CH₃. In certain embodiments R is H, R1 isH, and R2 is CH₃.

In one embodiment, the present invention provides a compound of Formula3 which is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound ofFormula 4 which is

or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a compound ofFormula 5, which is

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound ofFormula 5A, which is:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound ofFormula 5B, which is:

or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a compound ofFormula 6 which is

or a pharmaceutically acceptable salt thereof. In one embodiment thepharmaceutical composition comprises a compound of Formula 6 as aneutral compound as a free base or zwitterion. In one embodiment, thepresent invention provides the compound of Formula 6 as a citrate salt.In still yet another embodiment, the present invention provides acompound of Formula 6 as free base in crystalline form characterized byan X-ray powder diffraction pattern obtained from a CuKα source(λ=1.54056 Å), which comprises peaks at: 15.5, 18.1, 18.3, 20.5, and22.9+/−0.2° in 2 theta, or 13.2, 15.5, 18.1, 18.3, 18.5, 20.5, 22.9, and23.6, 23.7, +/−0.2° in 2 theta, or 13.2, 15.5, 18.1, 18.3, 18.5, 19.0,20.5, 22.9, 23.6, 23.6, 23.7, 24.7, and 26.5+/−0.2° in 2 theta.

In still yet another embodiment, the present invention provides acompound of Formula 6 as(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate (1:1:1) in crystallineform characterized by an X-ray powder diffraction pattern obtained froma CuKα source (λ=1.54056 Å), which comprises peaks at: 18.6, 19.1, 21.0,and 22.4+/−0.2° in 2 theta, or 7.4, 11.0, 18.6, 19.1, 21.0, 21.9, 22.4,and 26.2+/−0.2° in 2 theta or 7.4, 11.0, 12.7, 16.8, 18.6, 19.1, 21.0,21.9, 22.4, and 26.2, +/−0.2° in 2 theta.

In another form, the present invention provides a composition comprisingsubstantially pure(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate (1:1:1) in crystallineform. Preferably the composition comprises greater than 80%(weight/weight) of(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate (1:1:1) in crystallineform. More preferably greater than 90% (weight/weight) of(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate (1:1:1) in crystallineform. Still more preferably greater than 95% (weight/weight) of(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate (1:1:1) in crystallineform.

In another form, the present invention provides a pharmaceuticalcomposition that includes a compound according to any one of Formulae 1to 6, or pharmaceutically acceptable salt thereof, and at least one of apharmaceutically acceptable carrier, diluent or excipient.

In one embodiment the pharmaceutical composition comprises a compound ofFormulae 1 to 6 as a neutral compound or zwitterion. In anotherembodiment the pharmaceutical composition comprises a compound ofFormulae 1 to 6 as a pharmaceutically acceptable salt. In yet anotherembodiment, the pharmaceutical composition comprises a compound ofFormulae 1 to 6 as a citrate salt.

In another form, the present invention provides a method of treating apatient in need of treatment for arthritis, more preferably rheumatoidarthritis. The method includes administering to the patient an effectiveamount of a pharmaceutical composition comprising a compound accordingto one of Formulae 1 to 6, or a pharmaceutically acceptable saltthereof.

In another form, the present invention provides a method of treating apatient for diabetic nephropathy. The method comprises administering tothe patient an effective amount of a compound according to one ofFormulae 1 to 6, or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a method of treating apatient for diabetic nephropathy. The method comprises administering tothe patient an effective amount of a pharmaceutical composition compoundcomprising a compound according to one of Formulae 1 to 6, or apharmaceutically acceptable salt thereof.

In another form the present invention provides a method of treating apatient for inflammatory bowel disease. The method comprisesadministering to the patient an effective amount of a pharmaceuticalcomposition compound comprising a compound according to one of Formulae1 to 6, or a pharmaceutically acceptable salt thereof.

In another form, the present invention provides a method of treating ina patient in need for an autoimmune condition mediated by JAK1inhibition. The treatment comprises administering to the patient aneffective amount of a compound of Formulae 1-6, or a pharmaceuticallyacceptable salt thereof.

Examples of conditions mediated by JAK1 inhibition and which can betreated according to the present invention include: diabeticnephropathy; Lupus, more preferably systemic Lupus erythematosus;Sjögren's Syndrome; and inflammatory bowel disease, more preferably,Crohn's Disease, and ulcerative colitis.

In another form, the present invention provides a method of treating apatient in need of treatment for arthritis. The method comprisesadministering to a patient in need an effective amount of a compoundaccording to any one of Formulae 1 to 6, or a pharmaceuticallyacceptable salt thereof. More preferred methods of treating arthritisinclude treating a patient for rheumatoid arthritis.

In another form, the present invention provides a method of treating apatient in need of treatment for a condition selected from: diabeticnephropathy; Lupus, more preferably systemic Lupus erythematosus;Sjögren's Syndrome; and inflammatory bowel disease, more preferably,Crohn's Disease and ulcerative colitis. The method comprisesadministering to the patient an effective amount of a compound accordingto any one Formulae 1 to 6, or a pharmaceutically acceptable saltthereof.

In another form, the present invention provides a method of treating apatient in need of treatment for cancer. The method comprisesadministering to a patient in need thereof an effective amount of acompound according to any one of Formulae 1 to 6.

In another form, the present invention provides compound according toany one of Formulae 1 to 6 for use in therapy.

In one embodiment, the therapy, for which the compound according to anyone of Formulae 1 to 6 can be used, is selected from: arthritis, morepreferably rheumatoid arthritis; diabetic nephropathy; Lupus, morepreferably systemic Lupus erythematosus; Sjögren's Syndrome; andinflammatory bowel disease, more preferably Crohn's Disease andulcerative colitis.

In another form, the present invention provides for the use of acompound according to any one of Formulae 1 to 6 in the manufacture of amedicament.

In one embodiment, the medicament is useful to treat arthritis. Inanother embodiment, the medicament is useful to treat rheumatoidarthritis. In yet another embodiment, the medicament is useful to treata condition selected from; diabetic nephropathy; Lupus, more preferablysystemic Lupus erythematosus; Sjögren's Syndrome; and inflammatory boweldisease, more preferably, Crohn's Disease and ulcerative colitis. In yetanother embodiment, the medicament is useful to treat diabeticnephropathy. In yet another embodiment, the medicament is useful totreat Lupus. In yet another embodiment, the medicament is useful totreat Sjögren's Syndrome. In still yet another embodiment, themedicament is useful to treat inflammatory bowel disease.

The term “pharmaceutically acceptable salt” as used herein refers to asalt of a compound of the invention considered to be acceptable forclinical and/or veterinary use. Examples of pharmaceutically acceptablesalts and common methodologies for preparing them can be found in P.Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selectionand Use, 2nd Revised Edition. Wiley-VCH, 2011, and S. M. Berge, et al.,“Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, Vol. 66, No.1, January 1977.

The pharmaceutical compositions for the present invention may beprepared by procedures known in the art using pharmaceuticallyacceptable additives. The term “pharmaceutically acceptable additive(s)”as used herein for the pharmaceutical compositions, refers to one ormore carriers, diluents, and excipients that are compatible with theother additives of the formulation and not deleterious to the patient.Pharmaceutical compositions and processes for their preparation areknown and examples can be found in Loyd, V., et al. eds. Remington: TheScience and Practice of Pharmacy 22^(nd) Ed., Mack Publishing Co., 2012.Non-limiting examples of pharmaceutically acceptable carriers, diluents,and excipients include the following: saline, water, starch, sugars,mannitol, and silica derivatives; binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, andpolyvinyl-pyrrolidone; kaolin and bentonite; polyethyl glycols.

Preferred pharmaceutical compositions can be formulated as a tablet,capsule, solution for oral administration, or solution for injection.The tablet, capsule, or solution can include a compound of the presentinvention in an amount effective for treating a patient in need oftreatment.

As used herein, the term “effective amount” refers to an amount that isa dosage, which is effective for treating a disorder, such as arthritis,an autoimmune disease or cancer. The attending physician orveterinarian, as one skilled in the art, can readily determine aneffective amount by the use of conventional techniques and by observingresults obtained under analogous circumstances. A number of factors canbe considered to determine the effective amount or dose; the factors,include, but not limited to whether the compound or its salt, will beadministered; the co-administration of other agents, if used; thepatient's species; its size, age, and general health; the degree ofinvolvement or the severity of the disorder; the response of theindividual patient; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of other concomitant medication; and other relevantcircumstances.

As used herein, the term “patient” refers to a mammal, fowl, or fish.Preferred mammals include a human, a companion mammal, such as a dog orcat or a domesticated animal or livestock, such as a cow, pig, horse,sheep, and goat.

The term “substantially pure” refers to a composition that is greaterthan 80% pure, more preferably greater than 90% pure, and still morepreferably greater than 95% pure on a weight per weight basis.

The compounds of the present invention can be used alone or combinedwith one or more additional therapeutic agents. For example thecompounds of the present invention can be combined with agents for thetreatment of inflammation and/or autoimmune diseases. Examples includeNSAIDs or COX-2 inhibitors, such as ibuprofen, aspirin, acetaminophen,celecoxib, naproxen, and ketoprofen; opioids, such as oxycodone andfentanyl; methotrexate; and corticosteroids, such as hydrocortisone,prednisolone, and prednisone.

The compounds can also be combined with one or more additionaltherapeutic agents effective for treating cancers. Examples includecisplatin, carboplatin, etoposide, gemcitabine, paclitaxel, vinorelbine,topotecan, irinotecan, cyclophosphamide, doxorubicin, vincristine, andmethotrexate.

The exemplified compounds and the additional therapeutic agent(s) can beadministered either together through the same delivery route and devicesuch as a single pill, capsule or tablet; or separately administeredeither at the same time in separate delivery devices or sequentially.

CHEMISTRY SECTION

The compounds of the present invention, or salts thereof, may beprepared by a variety of procedures, some of which are illustrated inthe Preparations, and the Examples below. The product(s) of each step inthe procedures below can be recovered by conventional methods, includingextraction, evaporation, precipitation, chromatography, filtration,trituration, and crystallization. The reagents and starting materialsare readily available to one of ordinary skill in the art. In thepreparations described below, the amine substituent can be protected tofacilitate the synthesis of the compounds described herein.

As used herein, the following terms have the meanings indicated: “AcOH”refers to glacial acetic acid, “EC₅₀” refers to the concentration of anagent which produces 50% response of the target activity compared to apredefined positive control compound (absolute EC₅₀); “EtOAc” refers toethyl acetate; “ES/MS” refers to electrospray mass spectroscopy; “DCM”refers to dichloromethane; DMF” refers to N,N-dimethylformamide; “DMSO”refers to dimethylsulfoxide; “GC-MS” refers to gas chromatography-massspectrometry; “GFP” refers to green fluorescent protein; “HEPES” refersto 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; “hr” or “hrs”refers to hour(s); “IC₅₀” refers to the concentration of an agent whichproduces 50% of the maximal inhibitory response possible for that agent(relative IC₅₀), or the concentration of an agent which produces 50%inhibition of the target activity compared to placebo control (absoluteIC₅₀); “LC-MS” refers to liquid chromatography-mass spectrometry; “MeOH”refers to methanol; “min” refers to minutes; “MS” refers to massspectroscopy; “MTBE” refers to methyl tert-butyl ether, “OAc” refers toacetate or acetate anion; “QD” refers to once-a-day; “RT or rt” refersto room temperature; “STAT1” refers to signal transducer and activatorof transcription 1; “THF” refers to tetrahydrofuran, and “TR-FRET”refers to time-resolved fluorescence energy transfer.

Various amine protecting functionalities are known in the art andinclude: carbamates such as C₁₋₅ alkyl carbamate, C₃₋₆ cycloalkylcarbamate, preferably a t-butyl carbamate, (BOC) or benzyl carbamate(CBZ); amides such as C₁₋₃ alkylamide, C₁₋₃ haloalkylamide, formamide oracetamide chloroacetamide, trifluoridoacetamide; and benzyl amines.Additional examples of amine protecting functionalities, methods ofpreparing the protected amine substituents, and methods for deprotectingthe amine substituents can be found in “Greene's Protective Groups inOrganic Synthesis”, 5th Ed., Wuts, P. G. M., Eds. John Wiley and Sons,2014. It will be recognized by those skilled in the art that otherfunctional groups, which can be readily converted to the amine group,can be used. Such functional groups, preparations, and transformationsof these groups can be found in “Comprehensive Organic Transformations:A Guide to Functional Group Preparations” by Larock. R. C, Wiley VCH,1999 and in “March's Advanced Organic Chemistry: Reactions, Mechanismsand Structure” Smith, M. B., Wiley-Interscience, 7th Ed., 2013.

Preparation 1 (2R)-2-(Trifluoromethyl)oxirane

Add acetic acid (0.89 mL, 0.052 eq) to a solution of(1S,2S)-(+)-1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)cobalt(II) (0.90 g, 0.0050 eq) in toluene (16.65 mL). Stir at rt for 30 min.Remove the solvent in vacuo. Add toluene (20 mL) and concentrate invacuo. Cool to 0° C. and add 2-(trifluoromethyl)oxirane (37.00 g, 330mmol; 80.0% ee, (2R) is the major enantiomer). Stir for five minutes andadd water (0.80 mL, 0.15 eq) dropwise. Slowly warm to rt and stirovernight. Vacuum distill at rt, and collect the title compound in acooled flask as a light yellow oil (28.10 g, 76%; 99.8% ee). ¹H NMR(CDCl₃) δ 2.92-2.94 (m, 1H), 2.98-3.01 (m, 1H), 3.41-3.46 (m, 1H).

Combine the title compound (0.13 g, 1.16 mmol) and MeOH (1.3 mL). Coolto 0° C., and add triethylamine (0.17 mL, 1.10 eq) and thiophenol (0.12mL, 1.05 eq). Stir the mixture for 30 min. Monitor the reaction viaGC-MS for the formation of 1,1,1-trifluoro-3-phenylsulfanyl-propan-2-ol;m/z=222. Analysis of the product via chiral LC-MS reveals that theisomeric purity of the product is 99.8% ee,(2S)-1,1,1-trifluoro-3-phenylsulfanyl-propan-2-ol is the majorenantiomer.

Preparation 2 1-Bromo-3,5-difluoro-2-nitrobenzene

Add nitric acid (fuming, 20 mL) drop-wise to a solution of1-bromo-3,5-difluorobenzene (35.00 mL, 304 mmol) in sulfuric acid (50mL) at 0° C. Slowly warm to rt and stir overnight. Pour the reactionmixture into a mixture of ice and water (600 mL). Slowly warm to rt. AddEtOAc (200 mL) and hexanes (100 mL). Stir until all the solids dissolve.Separate the layers. Wash the organic layer with saturated aqueoussodium chloride, dry over Na₂SO₄, filter, and concentrate the filtratein vacuo to give the title compound as a yellow oil (57.37 g, 79%).GC-MS m/z=(⁷⁹Br/⁸¹Br) 237, 239 (M+H).

Preparation 3 3-Bromo-5-fluoro-N-methyl-2-nitroaniline

Add 2 M monomethylamine in tetrahydrofuran (92 mL, 2.00 eq) to asolution of 1-bromo-3,5-difluoro-2-nitrobenzene (21.90 g, 92 mmol) in1,4-dioxane (92 mL). Stir at rt for 45 min. Add water; then extract withEtOAc. Collect the organic extracts and wash with saturated aqueoussodium chloride. Dry over anhydrous Na₂SO₄, filter, and concentrate thefiltrate in vacuo to provide a residue. Subject the residue to normalphase chromatography, eluting with a 20-40% DCM in hexanes gradient, togive the title compound as an orange solid (16.95 g, 74%). MS (ES)m/z=(⁷⁹Br/⁸¹Br) 249/251 (M+H).

Preparation 4 tert-Butyl{cis-4-[3-bromo-5-(methylamino)-4-nitrophenoxy]cyclohexyl}carbamate

Combine 3-bromo-5-fluoro-N-methyl-2-nitroaniline (75.04 g, 301 mmol),tert-butyl (cis-4-hydroxycyclohexyl)carbamate (89.52 g, 1.38 eq),tetra(n-butyl)ammonium bisulfate (15.58 g, 0.15 eq) in DCM (975 mL) and5 M aqueous sodium hydroxide (241 mL). Stir rapidly at 37° C. undernitrogen for five days. Cool to rt. Dilute with DCM (200 mL) and water(400 mL). Separate the layers. Extract the aqueous with DCM (3×100 mL).Wash the combined organic extracts with saturated aqueous sodiumchloride, dry over anhydrous Na₂SO₄, filter, and concentrate thefiltrate in vacuo to provide a residue. Subject the residue to normalphase chromatography, eluting with a 0-40% EtOAc in hexanes gradient, togive the title compound as an orange solid (68.57 g, 51%). MS (ES)m/z=(⁷⁹Br/⁸¹Br) 442/444 (M−H).

Preparation 5 tert-Butyl{cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}carbamate

Combine tert-butyl{cis-4-[3-bromo-5-(methylamino)-4-nitrophenoxy]cyclohexyl}carbamate(76.92 g, 173 mmol) and platinum (5% on carbon sulfided, 3.85 g) intetrahydrofuran (923 mL) in a Parr® reactor. Stir at rt under H₂ (414kPa) for three days. Filter through diatomaceous earth. Wash thediatomaceous earth with THF. Add trimethylorthoformate (165 mL, 8.70 eq)to the combined THF filtrates. Stir for 22 hours at 63° C. Concentratethe majority of the reaction mixture in vacuo. Dilute with water (400mL) and EtOAc (400 mL). Basify with aqueous sodium carbonate to adjustthe pH to 9. Separate the layers. Extract the aqueous with EtOAc (2×200mL). Dry the combined organic extracts over anhydrous Na₂SO₄, filter,and concentrate the filtrate in vacuo. Dilute the residue with methyltert-butyl ether (400 mL) and sonicate for 30 minutes. Filter, wash withmethyl tert-butyl ether, and dry under vacuum to give the title compoundas a light brown solid (52.02 g, 71%). MS (ES) m/z=(⁷⁹Br/⁸¹Br) 424/426(M+H).

Preparation 6cis-4-[(4-Bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexanamine

Add trifluoroacetic acid (666 mL) slowly to a solution of tert-butyl{cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}carbamate(222 g, 497 mmol) in DCM (1110 mL) at 0° C. Slowly warm the mixture tort and stir overnight. Concentrate the mixture in vacuo. Add water (250mL) and basify with 50% aqueous sodium hydroxide to adjust the pH to 10.Add water (250 mL). Extract with 20% MeOH in DCM (1500 mL, then 500 mL,then 250 mL). Wash the combined organic extracts with 2 M aqueous sodiumhydroxide, dry over anhydrous MgSO₄, filter, and concentrate thefiltrate to give the title compound as a brown solid (155 g, 91%). MS(ES) m/z=(⁷⁹Br/⁸¹Br) 324/326 (M+H).

Preparation 7(2R)-3-({cis-4-[(4-Bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol

Add (2R)-2-(trifluoromethyl)oxirane (73.29 g, 1.50 eq) to a solution ofcis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexanamine (150.4g, 436 mmol) in MeOH (1053 mL). Stir at rt overnight. Concentrate thereaction mixture in vacuo to provide a residue. Subject the residue tonormal phase chromatography, eluting with a 0-10% EtOH in DCM gradient,to give the title compound as an off-white solid (98.10 g, 52%). MS (ES)m/z=(⁷⁹Br/⁸¹Br) 436/438 (M+H).

Preparation 8 1-(3-Methoxypropyl)-5-methyl-3-nitro-1H-pyrazole

Add acetonitrile (56 mL) to a mixture of 5-methyl-3-nitro-1H-pyrazole(3.0 g, 22 mmol), potassium carbonate (6.2 g, 2.0 eq), and1-bromo-3-methoxypropane (3.8 g, 1.1 eq). Stir at 65° C. overnight. Coolto rt. Add EtOAc (˜50 mL) and filter. Concentrate the filtrate in vacuo.Subject the residue to normal phase chromatography, eluting with 35%EtOAc in hexanes, to give the title compound (3.3 g, 70%). MS (ES)m/z=200 (M+H).

Preparation 9 1-(3-Methoxypropyl)-5-methyl-1H-pyrazol-3-amine

Add palladium on charcoal (5% w/w, 0.38 g) to a 500 mL Parr® reactor.Purge reactor with N₂ and add EtOH (100 mL). Add a solution of1-(3-methoxypropyl)-5-methyl-3-nitro-1H-pyrazole (3.3 g, 17 mmol) inEtOH (100 mL). Stir at rt under H₂ (60 psi) for two hours. Filterthrough diatomaceous earth. Concentrate the filtrate in vacuo to givethe title compound as an orange oil (2.7 g, 96%). MS (ES) m/z=170 (M+H).

Preparation 10 1-(2-Methoxyethyl)-5-methyl-3-nitro-1H-pyrazole

Add acetonitrile (35 mL) to a mixture of 5-methyl-3-nitro-1H-pyrazole(0.95 g, 7.1 mmol), potassium carbonate (2.0 g, 2.0 eq), and1-bromo-2-methoxyethane (2.0 mL, 3.0 eq). Stir at 75° C. for threehours. Cool to rt. Add diethyl ether (˜35 mL) and filter. Rinse thesolids with EtOAc (2×25 mL). Concentrate the filtrate in vacuo toprovide a residue. Subject the residue to normal phase chromatography,eluting with a 0-100% EtOAc in hexanes gradient, to give the titlecompound as a yellow oil (1.1 g, 64%). MS (ES) m/z=186 (M+H).

Preparation 11 1-(2-Methoxyethyl)-5-methyl-1H-pyrazol-3-amine

Add palladium on charcoal (10% w/w, 0.38 g) to a flask. Purge with N₂and add EtOH (10 mL). Add a solution of1-(2-methoxyethyl)-5-methyl-3-nitro-1H-pyrazole (0.86 g, 4.6 mmol) inEtOH (40 mL). Stir at rt under H₂ (balloon) overnight. Filter throughdiatomaceous earth. Concentrate the filtrate in vacuo to give the titlecompound as a brown oil (0.68 g, 84%). MS (ES) m/z=156 (M+H).

Preparation 12 1-(5-Methyl-3-nitro-1H-pyrazol-1-yl)propan-2-ol

Add acetonitrile (75 mL) to a mixture of 5-methyl-3-nitro-1H-pyrazole(2.0 g, 15 mmol), potassium carbonate (4.1 g, 2.0 eq), and1-chloro-2-propanol (3.8 mL, 3.0 eq). Stir at 85° C. overnight. Cool tort. Filter and rinse the solids with EtOAc. Concentrate the filtrate invacuo to provide a residue. Subject the residue to normal phasechromatography, eluting with 50% EtOAc in hexanes, to give the titlecompound (2.0 g, 65%). MS (ES) m/z=186 (M+H).

Preparation 13 1-(3-Amino-5-methyl-1H-pyrazol-1-yl)propan-2-ol

Add palladium on charcoal (10% w/w, 0.35 g) to a flask. Purge with N₂and add EtOH (50 mL). Add a solution of1-(5-methyl-3-nitro-1H-pyrazol-1-yl)propan-2-ol (2.0 g, 11 mmol) in EtOH(150 mL). Stir at rt under H₂ (balloon) overnight. Filter throughdiatomaceous earth. Concentrate the filtrate in vacuo to give the titlecompound as a pink oil (1.2 g, 69%). MS (ES) m/z=156 (M+H).

Preparation 14 (2S)-1-(5-Methyl-3-nitro-1H-pyrazol-1-yl)propan-2-ol

Add acetonitrile (45 mL) to a mixture of 5-methyl-3-nitro-1H-pyrazole(1.2 g, 9.0 mmol), potassium carbonate (2.5 g, 2.0 eq), and(S)-1-chloro-2-propanol (0.98 g, 1.2 eq). Stir at 85° C. for four days.Cool to rt. Filter to collect the solid and rinse the solid with EtOAc,then discard the solid. Collect and concentrate the filtrate in vacuo toprovide a residue. Subject the residue to normal phase chromatography,eluting with 50% EtOAc in hexanes, to give the title compound as a whitesolid (1.1 g, 67%). MS (ES) m/z=186 (M+H).

Preparation 15 (2S)-1-(3-Amino-5-methyl-1H-pyrazol-1-yl)propan-2-ol

Add palladium on charcoal (10% w/w, 0.22 g) to a flask. Add a solutionof (2S)-1-(5-methyl-3-nitro-1H-pyrazol-1-yl)propan-2-ol (1.1 g, 6.0mmol) in EtOH (50 mL). Stir at rt under H₂ (balloon) overnight. Filterthrough diatomaceous earth. Wash the solids with MeOH. Concentrate thefiltrate in vacuo to give the title compound (0.89 g, 95%). MS (ES)m/z=156 (M+H).

Preparation 16 (2R)-1-(5-Methyl-3-nitro-1H-pyrazol-1-yl)propan-2-ol

Add acetonitrile (41 mL) to a mixture of 5-methyl-3-nitro-1H-pyrazole(1.1 g, 8.2 mmol), potassium carbonate (2.3 g, 2.0 eq), and(R)-1-chloro-2-propanol (0.92 mL, 1.3 eq). Stir at 85° C. overnight.Cool to rt. Filter and rinse the solids with EtOAc. Concentrate thefiltrate in vacuo to provide a residue. Subject the residue to normalphase chromatography, eluting with 50% EtOAc in hexanes, to give thetitle compound as a white solid (0.74 g, 48%). MS (ES) m/Z=186 (M+H).

Preparation 17 (2R)-1-(3-Amino-5-methyl-1H-pyrazol-1-yl)propan-2-ol

Add palladium on charcoal (10% w/w, 0.15 g) to a flask. Add a solutionof (2R)-1-(5-methyl-3-nitro-1H-pyrazol-1-yl)propan-2-ol (0.74 g, 4.0mmol) in EtOH (33 mL). Stir at rt under H₂ (balloon) overnight. Filterthrough diatomaceous earth. Wash the solids with MeOH. Concentrate thefiltrate in vacuo to give the title compound as a yellow solid (0.58 g,95%). MS (ES) m/z=156 (M+H).

Preparation 18 Ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate

Combine diisopropylamine (55 mL, 1.36 eq) and 2-methyltetrahydrofuran(500 mL). Cool to −20° C. under N₂. Add 2.5 M n-butyllithium in hexanes(150 mL, 1.30 eq) dropwise over 10 min, then stir the solution for at−20° C. for an additional 15 min. Transfer the solution via cannula over20 min to a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate(50 mL, 287 mmol) in 2-methyltetrahydrofuran (500 mL) at −40° C. Stirthe solution at −40° C. for ten min. Add a solution of iodomethane (30mL, 1.68 eq) in 2-methyltetrahydrofuran (60 mL) dropwise over ten min.Stir at −40° C. for one hr. Allow to slowly warm to rt and stirovernight. Quench with saturated aqueous ammonium chloride (150 mL).Separate the layers. Extract the aqueous layer with methyl tert-butylether (50 mL). Dry the combined organic layers over anhydrous Na₂SO₄,filter, and concentrate in vacuo to give the title compound as a yellowoil (63.3 g, 97%). ¹H NMR (CDCl3) δ 1.16 (s, 3H), 1.20-1.25 (m, 3H),1.42-1.66 (m, 6H), 2.07-2.14 (m, 2H), 3.91 (s, 4H), 4.08-4.15 (m, 2H).

Preparation 19 8-Methyl-1,4-dioxaspiro[4.5]decane-8-carboxylic Acid

Combine ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (20 g, 88mmol). MeOH (100 mL), and 3 M sodium hydroxide in water (140 mL). Heatthe reaction mixture at reflux overnight. Concentrate in vacuo anddilute with water (150 mL) and methyl tert-butyl ether (50 mL). Separatethe layers and discard the organic layer. Acidify the aqueous layer with3% w/w aqueous hydrochloric acid to adjust pH to 2. Extract with methyltert-butyl ether (3×100 mL). Dry the combined organics over anhydrousNa₂SO₄, filter, and concentrate in vacuo to give the title compound as ayellow oily solid (12.6 g, 72%). ¹H NMR (CDCl3) δ 1.25 (s, 3H),1.47-1.60 (m, 2H), 1.65-1.70 (m, 4H), 2.08-2.17 (m, 2H), 3.93 (s, 4H).

Preparation 20 Prop-2-en-1-yl(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)carbamate

Combine 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid (12 g, 60mmol) and acetonitrile (200 mL). Add triethylamine (25.5 mL, 3.11 eq)and diphenylphosphoryl azide (15 mL, 1.18 eq). Stir at rt under N₂ fortwo hours. Add allyl alcohol (25 mL, 6.25 eq). Stir the reaction mixtureat reflux overnight. Concentrate in vacuo and dilute with water (150 mL)and methyl tert-butyl ether (150 mL). Separate the layers. Extract theaqueous layer with methyl tert-butyl ether (2×100 mL). Dry the combinedorganics over anhydrous Na₂SO₄, filter, and concentrate in vacuo to givethe title compound as a brown oil (10.8 g, 71%). ¹H NMR (CDCl3) δ 1.34(s, 3H), 1.57-1.69 (m, 6H), 1.98-2.11 (m, 2H), 3.92-3.93 (m, 4H),4.48-4.66 (m, 3H), 5.16-5.32 (m, 2H), 5.82-5.99 (m, 1H).

Preparation 21 Prop-2-en-1-yl (1-methyl-4-oxocyclohexyl)carbamate

Combine prop-2-en-1-yl (8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)carbamate(10.5 g, 41 mmol), acetone (30 mL), and water (3 mL). Add 35%hydrochloric acid (2.7 mL). Stir at rt overnight. Concentrate thereaction mixture in vacuo to remove the acetone. Dilute with methyltert-butyl ether (100 mL). Basify with 6 M aqueous potassium carbonateto adjust pH to 8. Separate the layers. Extract the aqueous layer withmethyl tert-butyl ether (2×20 mL). Dry the combined organics overanhydrous Na₂SO₄, filter, and concentrate in vacuo to provide a residue.Subject the residue to normal phase chromatography, eluting with agradient of 20-100% methyl tert-butyl ether in hexanes to give the titlecompound as a colorless oil (6.0 g, 69%). ¹H NMR (CDCl3) δ 1.44 (s, 3H),1.76-1.88 (m, 2H), 2.24-2.51 (m, 6H), 4.54 (d, 2H), 4.78 (s, 1H),5.20-5.35 (m, 2H), 5.85-6.00 (m, 1H).

Preparation 22 Prop-2-en-1-yl(cis-4-hydroxy-1-methylcyclohexyl)carbamate

Add 0.1 M monopotassium phosphate buffer (pH 7, 500 mL), MgSO₄ (0.12 g),NADP (0.27 g), and ketoreductase-P1-B10 (0.32 g) to a solution ofprop-2-en-1-yl (1-methyl-4-oxocyclohexyl)carbamate (32.8 g, 155 mmol) inisopropanol (110 mL). Stir at 35° C. for 24 hours. Extract with EtOAc.Dry the organics over anhydrous MgSO₄, filter, and concentrate thefiltrate in vacuo to give the title compound as a yellow oil (32.41 g,98%). ¹H NMR (CDCl3) δ 1.18-1.50 (m, 7H), 1.57-1.88 (m, 3H), 1.98-2.14(m, 2H), 3.55-3.65 (m, 1H), 4.46-4.66 (m, 3H), 5.17-5.32 (m, 2H),5.83-5.96 (m, 1H). The proton multiplet at 3.55-3.65 ppm is known to bein the cis configuration.

Preparation 23 Prop-2-en-1-yl{cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]-1-methylcyclohexyl}carbamate

Add 5 M aqueous sodium hydroxide (270 mL) and tetra(n-butyl)ammoniumbisulfate (7.50 g, 0.18 eq) to a solution of3-bromo-5-fluoro-N-methyl-2-nitroaniline (30.00 g, 120 mmol) andprop-2-en-1-yl (cis-4-hydroxy-1-methylcyclohexyl)carbamate (33.00 g,1.28 eq) in DCM (300 mL). Stir the mixture rapidly at rt for 24 hours.Add tetrabutylammonium hydrogen sulfate (7.50 g, 0.18 eq). Stir rapidlyat rt overnight. Dilute with water (20 mL). Separate the layers. Extractthe aqueous layer with DCM (2×150 mL). Wash the combined organicextracts with 5% w/w aqueous sodium chloride (200 mL) and water (200mL); then concentrate the organic extracts in vacuo. Combine theconcentrated organic extracts and acetic acid (650 mL). Addtrimethylorthoformate (45 mL). Stir at 90° C. for 2.5 hrs undernitrogen. Dilute with EtOAc (500 mL). Filter through a pad ofdiatomaceous earth. Wash the pad with EtOAc. Concentrate the combinedfiltrates in vacuo. Dilute with 2 M aqueous dipotassium phosphate (60mL) and 2-methyltetrahydrofuran (60 mL). Stir for 20 min, then filterthrough diatomaceous earth. Separate the layers. Extract the aqueouslayer with 2-methyltetrahydrofuran (2×20 mL). Combine the organicextracts, wash with water, and concentrate in vacuo. Dilute with1-methyl-2-pyrrolidinone (100 mL) and stir to obtain a homogenousmixture. Dropwise add the mixture to water (1200 mL) over 30 min. Stirfor 30 min, filter to collect the solid, and wash the solid with water.Dissolve the solid in 2-methyltetrahydrofuran (250 mL) and concentratein vacuo. Dilute the solution with isopropanol (3×150 mL) andconcentrate in vacuo. Dilute the solution with 2-methyltetrahydrofuran(10 mL) and concentrate in vacuo to give the title compound as an oily,brown residue (31.5 g, 74%). MS (ES) m/z=(⁷⁹Br/⁸¹Br) 422/424 (M+H).

Preparation 24cis-4-[(4-Bromo-1-methyl-1H-benzimidazol-6-yl)oxy]-1-methylcyclohexanamine

Combine prop-2-en-1-yl{cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]-1-methylcyclohexyl}carbamate(30 g, 71 mmol), bis(dibenzylideneacetone)palladium (0.50 g, 0.017 eq),1,4-bis(diphenylphosphino)butane (0.50 g, 0.022 eq), and thiosalicylicacid (15 g, 1.90 eq) in 2-methyltetrahydrofuran (700 mL). Heat thereaction mixture at 50° C. for one hour. Dilute with water (300 mL) andmethyl tert-butyl ether (300 mL). Acidify with 35% hydrochloric acid toadjust pH to 2. Separate the layers and discard the organic layer.Dilute the aqueous layer with EtOAc (20 mL) and stir for ten min.Separate the layers and discard the organics. Dilute the aqueous layerwith DCM (150 mL) and stir for ten min. Separate the layers and discardthe organic layer. Basify the aqueous layer with sodium hydroxide.Filter; collect the solid; then subject the resulting solid to normalphase chromatography, eluting with 5% 2 M ammoniated MeOH in DCM, togive the title compound (12.0 g, 50%). MS (ES) m/z=(⁷⁹Br/⁸¹Br) 338/340(M+H).

Preparation 25(2R)-3-({cis-4-[(4-Bromo-1-methyl-1H-benzimidazol-6-yl)oxy]-1-methylcyclohexyl}amino)-1,1,1-trifluoropropan-2-ol

Combinecis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]-1-methylcyclohexanamine(11.6 g, 34 mmol), (2R)-2-(trifluoromethyl)oxirane (4.00 g, 1.05 eq),EtOH (45 mL), and water (45 mL) in a glass pressure reactor. Seal andheat the reaction mixture at 90° C. for one hr. Allow to cool to rt. Add(2R)-2-(trifluoromethyl)oxirane (0.44 g, 0.12 eq). Seal and heat thereaction mixture at 90° C. for one hr. Concentrate in vacuo. Dilute withwater (100 mL), methyl tert-butyl ether (20 mL) and EtOAc (20 mL).Acidify with 35% aqueous hydrochloric acid to adjust pH to 2 and stiruntil a complete solution is achieved. Separate the layers and discardthe organic layer. Dilute the aqueous layer with methyl tert-butyl ether(40 mL). Separate the layers and discard the organic layer. Basify theaqueous layer with 50% w/w aqueous sodium hydroxide to adjust pH to 10.Extract the aqueous layer with EtOAc (2×50 mL). Combine the organicextracts and concentrate in vacuo. Crystallize a solid from EtOAc (50mL). Filter to collect the solid, then wash the resulting solid withEtOAc to give the title compound as a white solid (6.3 g, 41%). MS (ES)m z=(⁷⁹Br/⁸¹Br) 450/452 (M+H).

Concentrate the filtrate from the crystallization mother liquor toprovide a residue. Subject the residue to normal phase chromatography,eluting with 5% 2 M ammoniated MeOH in EtOAc, to give additional titlecompound as an off-white solid (3.3 g, 21%). MS (ES) m/z=(⁷⁹Br/⁸¹Br)450/452 (M+H).

Preparation 26 (2R)-2-(Difluoromethyl)-1,4-dioxaspiro[4.5]decane

Dissolve (3R)-1,4-dioxaspiro[4.5]decane-3-carbaldehyde (15.98 g, 89.19mmol) in DCM (80 mL). Place under N₂ and cool the solution to 0° C.Cautiously add diethylaminosulfur trifluoride (15 mL, 1.2 eq) dropwise.Allow to slowly warm to rt and stir overnight. Slowly pour the mixtureinto a stirring mixture of crushed ice, saturated aqueous sodiumbicarbonate, and DCM. Add dipotassium phosphate (5 g) and portion-wiseadditions of potassium carbonate, maintaining pH ˜7-8, until no morebubbling is observed. Stir for 20 min. Separate the layers. Extract theaqueous layer with DCM (3×). Wash the combined organic extracts with 1Maqueous sodium bisulfite and saturated aqueous sodium chloride. Dry theorganics over anhydrous Na₂SO₄, filter, and concentrate the filtrate invacuo to give the title compound as an amber oil (17.37 g, 93%). GC-MSm/z=192.

Preparation 27 (2R)-3,3-Difluoro-2-hydroxypropyl4-methylbenzenesulfonate

Dissolve (2R)-2-(difluoromethyl)-1,4-dioxaspiro[4.5]decane (9.08 g, 47.2mmol) in MeOH (250 mL). Add p-toluenesulfonic acid monohydrate (0.70 g,0.1 eq). Stir at rt for one week. Add sodium bicarbonate (0.60 g). Stirfor one hr. Add silica gel and trimethylamine (3 mL). Stir for ten min.Concentrate in vacuo and purify by normal phase chromatography, elutingwith a 15-100% EtOAc in hexanes gradient, to give(2R)-3,3-difluoropropane-1,2-diol as a yellow oil (2.95 g).

Dissolve (2R)-3,3-difluoropropane-1,2-diol (2.0 g, 15.2 mmol) in DCM (40mL). Place under nitrogen and cool the solution to 0° C. Add2,6-lutidine (8.0 mL, 4.5 eq). Add p-toluenesulfonyl chloride (3.0 g,1.0 eq) portion-wise. Allow to slowly warm to rt and stir for two days.Cool to −78° C. and add trimethylsilyl trifluoromethanesulfonate (1.5mL, 0.5 eq) dropwise. Allow to warm to 0° C. over 40 min. Addtrimethylsilyl trifluoromethanesulfonate (1.5 mL, 0.5 eq) dropwise. Stirfor 30 min and quench with MeOH (5 mL). Dilute with DCM and add asolution of sodium phosphate (4.9 g) in water (75 mL). Adjust the pH to˜3 with 2M aqueous potassium bisulfate. Separate the layers. Extract theaqueous layer with diethyl ether. Dry the organic extracts overanhydrous Na₂SO₄, filter, and concentrate the filtrate in vacuo. Addethylene glycol (1 mL) and silica gel (˜20 g). Concentrate in vacuo toprovide a residue. Subject the residue to normal phase chromatography,eluting with a 20-100% B in A gradient (A: hexanes, B: 6:3:1hexanes:DCM:THF), to give the title compound (1.37 g, 16%). GC-MSm/z=266.

Preparation 286-[(cis-4-Aminocyclohexyl)oxy]-N-(1,5-dimethyl-1H-pyrazol-3-yl)-1-methyl-1H-benzimidazol-4-amine

Combinecis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexanamine (25.70g, 79.27 mmol), 1,5-dimethyl-1H-pyrazol-3-amine (9.08 g, 1.0 eq),potassium carbonate (28.48 g, 2.6 eq),2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(8.60 g, 0.20 eq), tris(dibenzylideneacetone)dipalladium(0) (3.63 g,0.050 eq), and acetic acid (0.14 mL) in tert-butyl alcohol (250 mL).Heat at reflux overnight. Concentrate the reaction mixture in vacuo. AddDCM and water; separate the layers. Dry the organics over anhydrousmagnesium sulfate, filter, and concentrate in vacuo. Triturate fromEtOAc and hexanes to give a tan solid. Subject the tan solid to normalphase chromatography, eluting with hexanes, then 5% MeOH in DCM, then20% 2M ammoniated MeOH in DCM, to give the title compound as a tan solid(21.71 g, 77%). MS (ES) m/z=355 (M+H).

Preparation 29 2-(3-Nitro-1H-pyrazol-1-yl)pyridine

In each of two separate vials, combine 3-nitro-1H-pyrazole (3.0 g, 27mmol), 2-fluoropyridine (2.9 mL, 1.3 eq), and triethylamine (4.6 mL, 1.2eq) in 1-methyl-2-pyrrolidinone (20 mL). Seal and stir at 180° C.overnight. Cool to rt. Combine the reaction mixtures and dilute withwater. Filter to collect a solid, wash the solid with water, and dryunder vacuum to give the title compound (5.9 g, 58%). MS (ES) m/z=191(M+H).

Preparation 30 1-Pyridin-2-yl-1H-pyrazol-3-amine

Add palladium on charcoal (10% w/w, 1.9 g) to a flask. Purge with N₂ andadd EtOH (200 mL). Add 2-(3-nitro-1H-pyrazol-1-yl)pyridine (2.5 g, 13mmol). Stir at rt under H₂ (balloon) overnight. Add a small amount ofdiatomaceous earth and stir for five min. Filter through a pad ofdiatomaceous earth and wash the pad with EtOH. Concentrate the filtratein vacuo to give the title compound as a brown solid (1.8 g, 85%). MS(ES) m/z=161 (M+H).

Preparation 31 1-(Methylsulfonyl)-3-nitro-1H-pyrazole

Combine 3-nitro-1H-pyrazole (3.0 g, 27 mmol), methanesulfonyl chloride(2.5 mL, 1.2 eq), and triethylamine (4.4 mL, 1.2 eq) in DCM (20 mL).Stir at rt for two hours. Dilute with DCM and saturated aqueous sodiumbicarbonate. Separate the layers. Wash the organic layer with water andbrine. Dry the organic layer over anhydrous MgSO₄, filter, andconcentrate the filtrate in vacuo to give the title compound as a brownsolid (3.7 g, 73%). ¹H NMR (DMSO-d6) δ 3.74 (s, 3H), 7.30 (d, J=2.9 Hz,1H), 8.55 (d, J=2.9 Hz, 1H).

Preparation 32 3-Nitro-1-tetrahydro-2H-pyran-3-yl-1H-pyrazole

Combine tetrahydropyran-3-ol (1.3 g, 13 mmol),1-(methylsulfonyl)-3-nitro-1H-pyrazole (2.4 g, 1.0 eq), and cesiumcarbonate (4.8 g, 1.2 eq) in acetonitrile (40 mL). Stir at 90° C.overnight. Concentrate the mixture in vacuo. Dilute with EtOAc andfilter through a pad of diatomaceous earth. Concentrate the filtrate invacuo to provide a residue. Subject the residue to C-18 reverse phasechromatography eluting with a gradient from 0% to 100% of (0.1% formicacid in acetonitrile) in (0.1% formic acid in water), to give the titlecompound (0.35 g, 14%). MS (ES) m/z=198 (M+H).

Preparation 33 1-(Tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-amine

Add palladium on charcoal (10% w/w, 0.10 g) to a flask. Purge with N₂and add EtOH (20 mL). Add 3-nitro-1-tetrahydro-2H-pyran-3-yl-1H-pyrazole(0.30 g, 1.5 mmol). Stir at rt under H₂ (balloon) for two hrs. Filterthrough diatomaceous earth and wash with EtOH. Concentrate the filtratein vacuo to give the title compound as a gray solid (0.24 g, 94%). MS(ES) m/z=168 (M+H).

Example 1(2R)-1,1,1-Trifluoro-3-({cis-4-[(4-{[1-(3-methoxypropyl)-5-methyl-1H-pyrazol-3-yl]amino}-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol

Combine(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(4.0 g, 9.2 mmol), 1-(3-methoxypropyl)-5-methyl-1H-pyrazol-3-amine (2.2g, 1.4 eq), potassium carbonate (3.2 g, 2.5 eq),2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl(0.92 g, 0.20 eq), tris(dibenzylideneacetone)dipalladium(0) (0.87 g,0.10 eq), and acetic acid (0.01 mL) in tert-butyl alcohol (46 mL). Heatat 90° C. overnight. Filter through a pad of diatomaceous earth and washthe pad with EtOAc. Concentrate the filtrate in vacuo to provide aresidue. Subject the residue to normal phase chromatography, elutingwith 5% MeOH in DCM, to give crude product. Further purify the crudeproduct by reverse phase chromatography, eluting with a 15-60% B in Agradient (A: 10 mM ammonium bicarbonate in MeOH, B: acetonitrile).Concentrate fractions containing product to remove a majority of theacetonitrile. Add EtOAc and separate the layers. Wash the organic layerwith saturated aqueous sodium chloride, dry over sodium sulfate, filterand concentrate the filtrate in vacuo. Further purify the product bynormal phase chromatography, eluting with a 5% MeOH in DCM, to give thetitle compound as a white solid (2.4 g, 49%). MS (ES) m/z=525 (M+H).

Example 2(2R)-1,1,1-Trifluoro-3-({cis-4-[(4-{[1-(2-methoxyethyl)-5-methyl-1H-pyrazol-3-yl]amino}-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol

Combine(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(1.4 g, 3.2 mmol), 1-(2-methoxyethyl)-5-methyl-1H-pyrazol-3-amine (0.69g, 1.4 eq), potassium carbonate (1.1 g, 2.6 eq),2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(0.35 g, 0.20 eq), tris(dibenzylideneacetone)dipalladium(0) (0.15 g,0.050 eq), and acetic acid (0.01 mL) in tert-butyl alcohol (32 mL). Heatat reflux overnight. Concentrate the reaction mixture in vacuo. Add DCMand water; separate the layers. Filter the organic layer throughISOLUTE® HM-N material, wash with DCM and EtOAc. Concentrate thefiltrate in vacuo to provide a residue. Subject the residue to normalphase chromatography, eluting with a 30-100% B in A gradient (A: DCM, B:15% 2M ammoniated MeOH in DCM), to give the title compound as anoff-white solid (0.91 g, 56%). MS (ES) m/z=511 (M+H).

Example 3(2R)-1,1,1-Trifluoro-3-[(cis-4-{[4-({1-(2-hydroxypropyl)-5-methyl-1H-pyrazol-3-yl}amino)-1-methyl-1H-benzimidazol-6-yl]oxy}cyclohexyl)amino]propan-2-ol

Combine(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(0.35 g, 0.80 mmol), 1-(3-amino-5-methyl-1H-pyrazol-1-yl)propan-2-ol(0.14 g, 1.1 eq), potassium carbonate (0.28 g, 2.5 eq),2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl(0.12 g, 0.30 eq), tris(dibenzylideneacetone)dipalladium(0) (0.055 g,0.075 eq), and acetic acid (0.01 mL) in tert-butyl alcohol (5.3 mL).Heat at 100° C. overnight. Concentrate the reaction mixture in vacuo toprovide a residue. Subject the residue to C-18 reverse phasechromatography, eluting with a gradient of 0%-80% of acetonitrile in (10mM ammonium bicarbonate in methanol). Concentrate fractions containingproduct (as a mixture of isomers) in vacuo to give the title compound asa white solid (0.29 g, 71%). MS (ES) m/z=511 (M+H).

Separate the isomers in the mixture using the following chiralchromatography conditions to give:

-   -   First eluting enantiomer 1 (0.12 g, 99% ee). MS (ES) m/z=511        (M+H), 75%/25% CO₂/isopropanol, 5 mL/min, 4.6×150 mm, Chiralpak        AD-H    -   Second eluting enantiomer 2 (0.11 g, 97% ee). MS (ES) m/z=511        (M+H), 75%/25% CO₂/isopropanol, 5 mL/min, 4.6×150 mm. Chiralpak        AD-H

Example 4(2R)-1,1,1-Trifluoro-3-[(cis-4-{[4-({1-[(2S)-2-hydroxypropyl]-5-methyl-1H-pyrazol-3-yl}amino)-1-methyl-1H-benzimidazol-6-yl]oxy}cyclohexyl)amino]propan-2-ol

Combine(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(0.40 g, 0.92 mmol),(2S)-1-(3-amino-5-methyl-1H-pyrazol-1-yl)propan-2-ol (0.17 g, 1.2 eq),potassium carbonate (0.33 g, 2.6 eq),2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(0.099 g, 0.20 eq), tris(dibenzylideneacetone)dipalladium(0) (0.042 g,0.050 eq), and acetic acid (0.01 mL) in tert-butyl alcohol (10 mL). Sealwith a crimp cap. Heat the mixture in a microwave reactor at 140° C. for60 min. Concentrate the reaction mixture in vacuo. Add DCM and water;separate the layers. Filter the organic layer through ISOLUTE® HM-Nmaterial, wash the material with DCM and EtOAc. Concentrate the filtratein vacuo to provide a residue. Triturate the residue with EtOAc/hexanesto give the title compound (0.44 g, 95%). MS (ES) m/z==511 (M+H).

Example 5(2R)-1,1,1-Trifluoro-3-[(cis-4-{[4-({1-[(2R)-2-hydroxypropyl]-5-methyl-1H-pyrazol-3-yl}amino)-1-methyl-1H-benzimidazol-6-yl]oxy}cyclohexyl)amino]propan-2-ol

Combine(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(0.15 g, 0.34 mmol),(2R)-1-(3-amino-5-methyl-1H-pyrazol-1-yl)propan-2-ol (0.064 g, 1.2 eq),potassium carbonate (0.12 g, 2.6 eq),2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(0.037 g, 0.20 eq), tris(dibenzylideneacetone)dipalladium(0) (0.016 g,0.050 eq), and acetic acid (0.01 mL) in tert-butyl alcohol (10 mL). Sealwith a crimp cap. Heat the mixture in a microwave reactor at 140° C. for60 min. Concentrate the mixture in vacuo to provide a residue. Add DCMand water to the residue and separate the layers. Filter the organiclayer through ISOLUTE® HM-N material; wash the material with DCM andEtOAc. Concentrate the filtrate in vacuo. Triturate from EtOAc/hexanesto give the title compound as a tan solid (0.11 g, 62%). MS (ES) m/z=511(M+H).

Example 6(2R)-1,1,1-Trifluoro-3-{[cis-4-({4-[(5-methoxy-1-methyl-1H-pyrazol-3-yl)amino]-1-methyl-1H-benzimidazol-6-yl}oxy)cyclohexyl]amino}propan-2-ol

Add 2-methylbutan-2-ol (120 mL) to a mixture of(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(10 g, 22.9 mmol), 5-methoxy-1-methyl-pyrazol-3-amine (3.6 g, 28.8mmol), tris(dibenzylideneacetone) dipalladium-(0) (1.8 g, 2 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine(1.3 g, 2.4 mmol) and potassium carbonate (9 g, 65 mmol). Degas themixture by bubbling N₂ gas through the mixture and then add acetic acid(118 uL, 2 mmol). Heat and stir the mixture under N₂ at 100° C. for 20hr. Cool to rt; evaporate the solvent; then add EtOAc (100 mL), water(50 mL), and charcoal (1 g). Stir the mixture for 15 min and filter themixture through diatomaceous earth. Collect the filtrate and separateorganic layer. Add water (100 mL) and concentrated hydrochloric acid toadjust the pH to 2. Add charcoal (1.5 g), stir the mixture 30 min andfilter the mixture through diatomaceous earth. Transfer filtrate to aseparator funnel and isolate the aqueous layer. Add concentratedammonium hydroxide solution over the aqueous layer to adjust the pH to10 to provide a pale cream solid. Subject the solid to silica gelchromatography eluting with a mixture of methylene chloride and MeOH(95:5). Collect the desired fractions and evaporate the solvent toprovide the title compound as pale cream material (6.5 g, 13 mmol) 64%yield.

Crystallize the title compound from cyclopentyl methyl ether (45 mL) togive(2R)-1,1,1-trifluoro-3-[[4-[7-[(5-methoxy-1-methyl-pyrazol-3-yl)amino]-3-methyl-benzimidazol-5-yl]oxycyclohexyl]amino]propan-2-ol(3.2 g, 6.5 mmol). Stir the mixture at 22° C. for 18 h. Evaporate thesolvent and dry the white solid to constant weight to afford the titlecompound as white solid (3.2 g, 6.4 mmol) in 99% yield. MS (m/z): 483.2(M+H). 1H NMR (300.16 MHz, DMSO): 8.13 (s, 1H), 7.90 (s, 1H), 7.46 (d,J=1.9 Hz, 1H), 6.46 (d, J=1.9 Hz, 1H), 5.49 (s, 1H), 4.45 (s, 1H), 3.83(s, 3H), 3.73 (s, 3H), 3.47 (s, 3H), 2.75-2.67 (m, 2H), 1.99-1.91 (m,2H), 1.67-1.54 (m, 7H).

Example 7(2R)-3-{[(cis-4-({4-[(Ethyl-5-methyl-1H-pyrazol-3-yl)amino]-1-methyl-1H-benzimidazol-6-yl}oxy)cyclohexyl]amino}-1,1,1-trifluoropropan-2-ol

Combine(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(1.36 g, 3.12 mmol), 1-ethyl-5-methyl-1H-pyrazol-3-amine (0.78 g, 2.0eq), potassium carbonate (1.12 g, 2.6 eq),2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(0.34 g, 0.20 eq), tris(dibenzylideneacetone)dipalladium(0) (0.14 g,0.050 eq), and acetic acid (0.01 mL) in tert-butyl alcohol (30 mL). Heatat reflux overnight. Concentrate the reaction mixture in vacuo. Add DCMand water; separate the layers. Filter the organic layer throughISOLUTE® HM-N material, washing with DCM. Concentrate the filtrate invacuo to provide a residue. Triturate the residue in EtOAc and hexanesto give the title compound (1.40 g, 94%). MS (ES) m/z=481 (M+H).

Example 8(2R)-1,1,1-Trifluoro-3-[(cis-1-methyl-4-{[1-methyl-4-(1H-pyrazol-3-ylamino)-1H-benzimidazol-6-yl]oxy}cyclohexyl)amino]propan-2-ol

Combine(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]-1-methylcyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(0.91 g, 2.02 mmol), 3-aminopyrazole (0.29 g, 1.70 eq), potassiumcarbonate (0.73 g, 2.6 eq),2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(0.22 g, 0.20 eq), tris(dibenzylideneacetone)dipalladium(0) (0.093 g,0.050 eq), and acetic acid (0.01 mL) in tert-butyl alcohol (20 mL).Reflux the mixture overnight. Concentrate the mixture in vacuo. Add DCMand water; separate the layers. Filter the organic layer throughISOLUTE® HM-N material, washing with DCM. Concentrate the filtrate invacuo to provide a residue. Subject the residue to normal phasechromatography, eluting with a 50-100% B in A gradient (A: methyltert-butyl ether, B: 15% 7M ammoniated MeOH in DCM), to give the titlecompound (0.67 g, 74%). MS (ES) m/z=453 (M+H).

Example 9(2R)-3-{[cis-4-({4-[(1,5-Dimethyl-1H-pyrazol-3-yl)amino]-1-methyl-1H-benzimidazol-6-yl}oxy)cyclohexyl]amino}-1,1-difluoropropan-2-ol

Combine (2R)-3,3-difluoro-2-hydroxypropyl 4-methylbenzenesulfonate (0.38g, 1.31 mmol) and6-[(cis-4-aminocyclohexyl)oxy]-N-(1,5-dimethyl-1H-pyrazol-3-yl)-1-methyl-1H-benzimidazol-4-amine(0.61 g, 1.30 eq) in acetonitrile (3 mL) and 2-propanol (3 mL). AddN,N-diisopropylethylamine (0.50 mL, 2.0 eq) and sodium iodide (0.015 g,0.1 eq). Heat at 65° C. overnight. Add (2R)-3,3-difluoro-2-hydroxypropyl4-methylbenzenesulfonate (0.065 g, 0.22 mmol) and heat at 65° C.overnight. Filter through diatomaceous earth. Wash the solids withEtOAc. Concentrate the filtrate in vacuo. Purify by reverse phasechromatography, eluting with a 0-90% acetonitrile in water gradient.Concentrate fractions containing product in vacuo to give the titlecompound as an off-white solid (0.40 g, 67%). MS (ES) m z=449 (M+H).

Example 10(2R)-1,1,1-Trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol

Combine(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(1.8 g, 4.1 mmol), 1-pyridin-2-yl-1H-pyrazol-3-amine (0.86 g, 1.3 eq),potassium carbonate (1.7 g, 2.9 eq),2-(di-tert-butylphosphino)-2′4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl(0.83 g, 0.41 eq), tris(dibenzylideneacetone)dipalladium(0) (0.38 g,0.10 eq), and acetic acid (0.03 mL) in tert-butyl alcohol (22 mL). Heatthe mixture at 90° C. for three hours. Cool the mixture to rt. Filterthrough a pad of diatomaceous earth and wash the pad with EtOAc.Concentrate the filtrate in vacuo to provide a residue. Subject theresidue to normal phase chromatography, eluting with a 0-10% MeOH in DCMgradient, to give the title compound (1.34 g, 63° %.). MS (ES) m/z=516(M+H).

Crystalline free base material can be obtained by dissolving the solidmaterial, which is prepared substantially as described above, in 2butanone (100 mass %) then heating the resulting mixture to 65° C. Allowthe mixture to cool to 20° C., and add heptane (100 mass %) to induceparticipation. Collect the resulting solid and wash with heptane, airdry for 15 minutes, then dry in the oven at 40° C. overnight to providethe title compound as an anhydrous crystalline free base in 62% yield.

X-Ray Powder Diffraction of Example 10

The XRD patterns of crystalline solids are obtained on a Bruker D4Endeavor X-ray powder diffractometer, equipped with a CuKa source(λ=1.54060 Å) and a Vantec detector, operating at 35 kV and 50 mA. Thesample is scanned between 4 and 40° in 2θ, with a step size of 0.0087°in 2θ and a scan rate of 0.5 seconds/step, and with 0.6 mm divergence,5.28 mm fixed anti-scatter, and 9.5 mm detector slits. The dry powder ispacked on a quartz sample holder and a smooth surface is obtained usinga glass slide. It is well known in the crystallography art that, for anygiven crystal form, the relative intensities of the diffraction peaksmay vary due to preferred orientation resulting from factors such ascrystal morphology and habit. Where the effects of preferred orientationare present, peak intensities are altered, but the characteristic peakpositions of the polymorph are unchanged. See, e.g. The U. S.Pharmacopeia 38—National Formulary 35 Chapter Characterization ofcrystalline and partially crystalline solids by X-ray powder diffraction(XRPD) Official May 1, 2015. Furthermore, it is also well known in thecrystallography art that for any given crystal form the angular peakpositions may vary slightly. For example, peak positions can shift dueto a variation in the temperature or humidity at which a sample isanalyzed, sample displacement, or the presence or absence of an internalstandard. In the present case, a peak position variability of ±0.2 in 2θwill take into account these potential variations without hindering theunequivocal identification of the indicated crystal form. Confirmationof a crystal form may be made based on any unique combination ofdistinguishing peaks (in units of ° 2θ), typically the more prominentpeaks. The crystal form diffraction patterns, collected at ambienttemperature and relative humidity, are adjusted based on NIST 675standard peaks at 8.85 and 26.77 degrees 2-theta.

Thus, a prepared sample of the free base compound of Example 10 ischaracterized by an XRD pattern using CuKa radiation as havingdiffraction peaks (2-theta values) as described in Table 1 below.Specifically the pattern contains a peak at 20.5 in combination with oneor more of the peaks selected from the group consisting of 15.5, 18.1,18.3, 18.5, 22.9 and 23.6 with a tolerance for the diffraction angles of0.2 degrees.

TABLE 1 X-ray powder diffraction peaks of Example 10 Peak Angle 2theta %Intensity 1 11.3 21% 2 13.2 37% 3 14.8 22% 4 15.5 63% 5 16.3 19% 6 18.163% 7 18.3 75% 8 18.5 56% 9 19.0 30% 10 19.3 27% 11 20.5 100%  12 20.819% 13 22.3 16% 14 22.9 86% 15 23.3 30% 16 23.6 49% 17 23.7 45% 18 24.736% 19 25.5 28% 20 26.5 33% 21 28.3 19% 22 31.0 17%

Examples 11A and 11B(2R)-1,1,1-Trifluoro-3-[(cis-4-{[1-methyl-4-({1-[(3R)-tetrahydro-2H-pyran-3-yl]-1H-pyrazol-3-yl}amino)-1H-benzimidazol-6-yl]oxy}cyclohexyl)amino]propan-2-ol

(2R)-1,1,1-Trifluoro-3-[(cis-4-{[1-methyl-4-({1-[(3S)-tetrahydro-2H-pyran-3-yl]-1H-pyrazol-3-yl})amino)-1H-benzimidazol-6-yl]oxy}cyclohexyl)amino]propan-2-ol

First prepare the compounds as a racemic mixture. Combine(2R)-3-({cis-4-[(4-bromo-1-methyl-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)-1,1,1-trifluoropropan-2-ol(0.62 g, 1.2 eq), 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-amine (0.20g, 1.2 mmol), potassium carbonate (0.42 g, 2.5 eq),2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl(0.18 g, 0.30 eq), tris(dibenzylideneacetone)dipalladium(0) (0.085 g,0.075 eq), and acetic acid (0.02 mL) in tert-butyl alcohol (6 mL). Heatat 100° C. for seven hrs. Allow the reaction mixture to cool to rt.Concentrate the reaction mixture in vacuo. Dilute with EtOAc. Filterthrough a pad of diatomaceous earth and wash the pad with EtOAc. Addsaturated aqueous sodium bicarbonate to the filtrate. Separate thelayers. Wash the organic layer with water and brine. Dry the organiclayer over anhydrous MgSO₄, filter, and concentrate the filtrate invacuo to provide a residue. Subject the residue to normal phasechromatography, eluting with a 0-30% MeOH in DCM gradient, to give thetitle compound (0.31 g, 49%). MS (ES) m/z=523 (M+H).

Separate the isomers by first preparing the5-(trifluoromethyl)oxazolidin-2-one derivative:

(5R)-3-(cis-4-{[1-Methyl-4-({1-[(3R)-tetrahydro-2H-pyran-3-yl]-1H-pyrazol-3-yl}amino)-1H-benzimidazol-6-yl]oxy}cyclohexyl)-5-(trifluoromethyl)-1,3-oxazolidin-2-one

and(5R)-3-(cis-4-{[1-Methyl-4-({1-[(3S)-tetrahydro-2H-pyran-3-yl]-1H-pyrazol-3-yl}amino)-1H-benzimidazol-6-yl]oxy}cyclohexyl)-5-(trifluoromethyl)-1,3-oxazolidin-2-one

Combine(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol(0.25 g, 0.42 mmol), 1,1′-carbonyldiimidazole (0.14 g, 2.0 eq), and4-dimethylaminopyridine (0.011 g, 0.21 eq) in DCM (2 mL). Stir at rt forthree days. Concentrate in vacuo to provide a residue. Subject theresidue to normal phase chromatography, eluting with a 0-20% MeOH in DCMgradient, to give racemic mixture of(5R)-3-(cis-4-{[1-methyl-4-({1-[tetrahydro-2H-pyran-3-yl]-1H-pyrazol-3-yl}amino)-1H-benzimidazol-6-yl]oxy}cyclohexyl)-5-(trifluoromethyl)-1,3-oxazolidin-2-one.Separate isomers by chiral chromatography using 60%/40% CO₂/isopropanol,5 mL/min, 4.6×150 mm, Lux Amylose-2.

Isomer 1 (0.10 g, 99% ee). Retention time 2.98 min. MS (ES) m/z=549(M+H)Isomer 2 (0.10 g, 99% ee). Retention time 4.83 min. MS (ES) m/z=549(M+H)

Isomer 1(2R)-1,1,1-Trifluoro-3-({cis-4-[(1-methyl-4-{[1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol

Combine(5R)-3-(cis-4-{[1-methyl-4-({1-[tetrahydro-2H-pyran-3-yl]-1H-pyrazol-3-yl}amino)-1H-benzimidazol-6-yl]oxy}cyclohexyl)-5-(trifluoromethyl)-1,3-oxazolidin-2-one(Isomer 1) (0.080 g, 0.15 mmol) and potassium trimethylsilanolate (0.041g, 2.0 eq) in THF (2 mL). Stir at 65° C. for three days. Add potassiumtrimethylsilanolate (0.018 g, 1.0 eq). Stir at 65° C. overnight. Allowto cool to rt. Dilute with a few drops of water and concentrate invacuo. Purify by C-18 reverse phase chromatography using 0%-100%acetonitrile in (10 mM ammonium bicarbonate in methanol) gradient, togive the title compound (0.055 g, 72%). MS (ES) m/z=523 (M+H).

Isomer 2(2R)-1,1,1-Trifluoro-3-({cis-4-[(1-methyl-4-{[1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol

Combine(5R)-3-(cis-4-{[1-methyl-4-({1-[tetrahydro-2H-pyran-3-yl]-1H-pyrazol-3-yl}amino)-1H-benzimidazol-6-yl]oxy}cyclohexyl)-5-(trifluoromethyl)-1,3-oxazolidin-2-one(Isomer 2) (0.080 g, 0.15 mmol) and potassium trimethylsilanolate (0.040g, 2.0 eq) in THF (2 mL). Stir at 65° C. for three days. Add potassiumtrimethylsilanolate (0.018 g, 1.0 eq). Stir at 65° C. overnight. Allowto cool to rt. Dilute with a few drops of water and concentrate invacuo. Purify by C-18 reverse phase chromatography using a 0%-100%acetonitrile in (10 mM ammonium bicarbonate in methanol) gradient, togive the title compound (0.058 g, 76%). MS (ES) m/z=523 (M+H).

Example 12(2R)-1,1,1-Trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate Hydrate (1:1:1)

Add 1.23 g of(2R)-1,1,1-Trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-olto 10 mL of 88% acetone while stirring at 1000 rpm/70° C., to obtain awhite slurry. Add 510 mg of citric acid dropwise. The white slurry turnsto a clear yellowish solution. Discontinue heating and stirring. Overthe next hour, a yellow solid slowly forms. Isolate the light yellowsolid by vacuum filtration. Dry the sample on the filter under airstream for 20 minutes to yield the title compound. (1.62 g, 93.6%)

X-Ray Powder Diffraction of Example 12:

The XRD patterns of crystalline solids are obtained on a Bruker D4Endeavor X-ray powder diffractometer, equipped with a CuKa source(λ=1.54060 Å) and a Vantec detector, operating at 35 kV and 50 mA. Thesample is scanned between 4 and 40° in 2θ, with a step size of 0.0087°in 20 and a scan rate of 0.5 seconds/step, and with 0.6 mm divergence,5.28 mm fixed anti-scatter, and 9.5 mm detector slits. The dry powder ispacked on a quartz sample holder and a smooth surface is obtained usinga glass slide. It is well known in the crystallography art that, for anygiven crystal form, the relative intensities of the diffraction peaksmay vary due to preferred orientation resulting from factors such ascrystal morphology and habit. Where the effects of preferred orientationare present, peak intensities are altered, but the characteristic peakpositions of the polymorph are unchanged. See, e.g. The U. S.Pharmacopeia 38—National Formulary 35 Chapter Characterization ofcrystalline and partially crystalline solids by X-ray powder diffraction(XRPD) Official May 1, 2015. Furthermore, it is also well known in thecrystallography art that for any given crystal form the angular peakpositions may vary slightly. For example, peak positions can shift dueto a variation in the temperature or humidity at which a sample isanalyzed, sample displacement, or the presence or absence of an internalstandard. In the present case, a peak position variability of +0.2 in 2θwill take into account these potential variations without hindering theunequivocal identification of the indicated crystal form. Confirmationof a crystal form may be made based on any unique combination ofdistinguishing peaks (in units of ° 2θ), typically the more prominentpeaks. The crystal form diffraction patterns, collected at ambienttemperature and relative humidity, are adjusted based on NIST 675standard peaks at 8.85 and 26.77 degrees 2-theta.

An XRD pattern of(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate (1:1:1) using CuKaradiation provides diffraction peaks (2-theta values) as described inTable 2 below, and in particular having peaks at 17.9 in combinationwith one or more of the peaks selected from the group consisting of26.1, 26.6, and 22.7; with a tolerance for the diffraction angles of 0.2degrees.

TABLE 2 X-ray powder diffraction peaks of the crystalline (2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol 2-hydroxypropane-1,2,3-tricarboxylate hydrate (1:1:1) Relative Intensity Peak Angle(°2-Theta) +/− 0.2° (% of most intense peak) 1 4.7  8% 2 9.5 40% 3 10.030% 4 11.2 29% 5 17.2 45% 6 17.9 100%  7 18.7 36% 8 22.7 52% 9 26.1100%  10 26.6 63%

Biological Section JAK1, JAK2 and JAK3 In Vitro Enzyme Assays

The JAK LanthaScreen™ Kinase Assay (Invitrogen) is used to determine theability of test compounds to inhibit JAK1, JAK2, and JAK3 kinaseactivity. These are TR-FRET assay formats that use long-lifetime terbiumlabeled antibody as the donor species and GFP-STAT1 as the acceptorspecies. Use the TR-FRET ratio to monitor JAK kinase activity where anincrease in phosphorylation of the GFP-STAT1 results in an increase inthe TR-FRET ratio. Perform the kinase reaction using a 12.5 μl reactionvolume in shallow black 384-well Proxiplate®. Add reagents to obtainfinal reaction conditions of 50 ml HEPES pH, 1.76 mM Triton X-100, ATP(20.0 μM for JAK1 and JAK3 or 5 μM for JAK2) enzyme assays, 10.0 mMMgCl₂, 1 mM EGTA and 0.01% Brij-35, 0.05 mM GFP-STAT1, 14 nM JAK1 enzymefor JAK1, 1.0 nM for JAK2 or 2.5 nM for JAK3 enzyme assays, and 4% DMSOand serial dilutions of test compound (diluted 1:3 from 20,000 to 1 nM).Following ATP/GFP-STAT1 addition, centrifuge the assay plates for 1minute at 1000 revolutions per minute (RPM). Allow the plates toincubate at RT for 60 minutes and then add 12.5 μl of a stopping buffercontaining 20 mM EDTA, 2 nM Terbium-anti-phosphorylated SignalTransducers and Activators of Transcription [phosphorylation Tyrosine701 amino acid] Antibody (Tb-anti-pSTAT1 [pTyr701], 0.67 mMtris(hydroxymethyl)aminoethane hydrochloride (Trizma®) pH 7.5, 0.02%NaN₃ and 0.01% nonylphenylpolyethylene glycol (Nonidet® P40). Incubateat RT for 90 min and read in an EnVision® plate reader with 340 nmwavelength excitation filter and emission filters of 520 nm and 495 nmwavelengths. Derive the ratio from the emission wavelength for theGFP-STAT1 which is measured at 520 nm versus the emission at 495 nm forthe (Tb-anti-pSTAT1 [pTyr701]. Derive the IC₅₀ value for each compoundusing percent inhibition data which is calculated from the reaction datarelative to on-plate controls (active enzyme versus enzyme inhibited at2.0 mM with tofacitinib). Use ACTIVITYBASE® 4.0 to fit the percentinhibition and ten-point compound concentration data to a four-parameterlogistic equation.

Following a protocol essentially as described above, the compounds ofthe Examples herein were tested. The compounds of the Examples exhibiteda IC₅₀ for JAK1 of less than 8 nM and are selective inhibitors of JAK1over JAK2, or JAK3 in vitro. The compounds of Examples 1 and 6 to 10exhibited the activity listed in Table 3.

TABLE 3 Example No. JAK1 IC₅₀ (nM) JAK2 IC₅₀ (nM) JAK3 IC₅₀ (nM) 1 3.25± 0.99 (n = 3) 1200 ± 550 (n = 3)  3720 ± 1300 (n = 3)  6 5.25 ± 1.11 (n= 5) 768 ± 220 (n = 5) 2540 ± 510 (n = 5) 7 5.43 ± 0.93 (n = 3)  901 ±99 (n = 3) 6160 ± 2020 (n = 3)  8 1.91 ± 0.75 (n = 4) 239 ± 150 (n = 4)1170 ± 470 (n = 4) 9 5.35 ± 0.23 (n = 5)  767 ± 39 (n = 5) 2140 ± 720 (n= 5) 10 1.49 ± 0.49 (n = 3) 220 ± 120 (n = 3)  660 ± 180 (n = 3)

The data demonstrate that the compounds of the Examples are inhibitorsof JAK1 enzyme and selective to JAK1 over JAK2 and JAK3 in vitro.

AlphaScreen SureFire Protocol p-STAT3-(p-Tyr705)-IL6-TF-1-JAK1Cell-Based Assay

The JAK1 cell based assay described below is used to determine the JAK1cellular potency of test compounds.

Cell preparation: Starve TF-1 cells in DMEM medium with 0.5% 26400 (FBS)and 1× Pen/Strep at 37° C. Plate 100K cells per well in BD 96 well blackplates with clear bottoms. Maintain the plates at RT for 30-60 minutesbefore incubating overnight at 37° C., and 5% CO₂. Count cells usingVi-Cell counter, using a cell suspension at 100 cells/mL and plated 100μL/well in Beckman Dickinson Biocoat plates (Catalog #354640).

Test compound preparation and treatment: Prepare compounds at 1:3 serialdilutions in DMSO and further dilute into the medium. Test compounds ina range of 10 point concentrations from 20,000 to 1 nM. Add dilutedcompound to corresponding cell plates. Incubate the plates at 37° C. for20 min. Add IL6 solution at the final concentration 30 ng/mL tocorresponding cell plates and continue to incubate at 37° C. for 30 min.Remove media and add 50 μL 1× lysis buffer to each well.

pSTAT3 detection: Perform the following steps sequentially: makeacceptor mix (activation buffer/reaction buffer/acceptor beads);transfer 4 μL lysate from 96 well plates to 384 well-Proxiplates; add 5μL acceptor mix to 384 proxiplate plate(s) and seal plates with aluminumseal; shake 1-2 minutes on plate shaker; incubate plate at RT for 2 hrwith gentle shaking; make donor mix (donor beads in dilution buffer);add 2 μL donor mix to assay plates; seal plates with aluminum seal;shake 1-2 minutes on plate shaker; incubate at RT for 2 hr with gentleshaking; read plate with Envision; protocol AlphaScreen Surefire 384.

Following a protocol essentially as described above, the compounds ofExamples 1, 2, and 6 were tested and exhibited the following activity asillustrated in Table 4 below.

TABLE 4 Example No. IC₅₀(nM) 1 0.154 ± 0.023 (n = 2) 2 0.275 ± 0.102 (n= 3) 6 0.168 ± 0.090 (n = 4)

The data in Table 4 demonstrate that the compounds of Examples 1, 2, and6 inhibit the JAK1 enzyme in a cell based assay provides support thatthe compounds of the Examples also inhibit the JAK1 enzyme in the cell.

Human Whole Blood Assays: Determination of pSTAT3 (JAK1) and pSTAT5(JAK2) in Lymphocytes and Monocytes

Human whole blood (HWB) assays were developed and validated to determinethe JAK1 and JAK2 selectivity of test compounds.

Dilute the test compounds, 10 points, (1:3) in DMSO 100% and a step downin PBS+0.1% BSA. Use Tofacitinib as a reference compound in each plate,as well as a maximum signal (stimulated wells) and a minimum signal (nostimulated wells) in order to normalize data. Obtain a pool of HWB from4 different healthy donors. Plate the blood in a 96 well plate using aTecan Evo 96w and incubate with test compounds for 1 h at RT. After thistime of incubation, stimulate HWB with both IL6 (206-IL, R&D System) andGM-CSF (PHC2015, Life Technologies) for 15 more minutes. Add a viabilitydye (65-0865, eBiosicience) (1:1000) using a Tecan Evo 96w (5×mix).

The final concentrations in the assay are the following: 100 (μM forcompounds, 50 μM for Tofacitinib, 0.1 μg/mL IL6, 0.038 μg/mL GM-CSF and1% DMSO. Lyse and fix HWB using a Lyse/fix buffer (558049, BectonDickinson) by adding 900 μL of lysis buffer using Tecan Evo 96w (mix 10×high speed). Incubate HWB in bath at 37° C. for 10 minutes. CentrifugeHWB at 500 G, 8 min and discard supernatant. Add cold MeOH using a TecanExo 96w in order to permeabilize cells. Incubate blood cells on iceduring 30 min. After this, wash cells 2× using Staining buffer (554656,Becton Dickinson), spin at 3000 rpm, 2 min. discard supernatant, and addthe following antibodies: Anti-Human CD4 PE, 1:100 (12-0048,eBioscience), Anti-Human CD33 eFluor® 450, 1:50 (48-0337, eBioscience),Phospho-STAT5 (Tyr694) (C71E5) Rabbit mAb, 1:100 (Alexa Fluor® 488Conjugate) (3939, Cell Signaling) and Phospho-STAT3 (Tyr705) (D3A7) XP™Rabbit mAb 1:200, (Alexa Fluor® 647 Conjugate) (4324, Cell Signaling).Incubate the antibodies for 1 h in dark at RT, then wash cells 2× andread on Cytometer Macsquant (Miltenyi Biotec). Gate the data on CD4+(lymphocytes) and CD4Low CD33Hi (monocytes), to measure the fluorescenceintensity from cells expressing pSTAT3 and pSTAT5, respectively. Analyzethe data using FlowJo v 10 and then normalize the median of fluorescenceversus maximum and minimum signal to determine the IC₅₀s. Use Graph PadPrism 5™ to represent the dose response curves.

Following a protocol essentially as described above, the compounds ofthe Examples herein were tested. The compounds of the Examples exhibitedgreater selectivity for JAK1 over JAK 2. The activity for the compoundsof Examples 6 to 10 are listed in Table 5.

TABLE 5 Example No. JAK1 IC₅₀(μM) JAK2 IC₅₀(μM) 6 3.65 ± 0.79 (n = 7)20.3 ± 6.3 (n = 6) 7 4.17 ± 1.87 (n = 6) 18.6 ± 6.1 (n = 5) 8  3.13 ±1.1 (n = 6) 9.63 ± 2.52 (n = 6)  9 4.53 ± 2.09 (n = 7) 16.9 ± 4.5 (n =6) 10 1.29 ± 0.64 (n = 3) 6.86 ± 2.13 (n = 3) 

The data in Table 5 demonstrate that the compounds of the Examples aremore potent for JAK1 over JAK2 in a human whole blood assay.

Rat PK/PD Assay

Male Wistar rats, 265-285 grams (Charles River) were used for oralgavage dosing. Dose the animals (Oral gavage) at 1.82 mL/kg (0.5 mL per275 grams). Formulate the compounds in 1% HEC vehicle containing 0.25%Tween 80 and 0.05% antifoam with 1.1 molar equivalent of methanesulfonicacid to form an in situ salt. Formulate compounds once per week, andstore at 4° C. At various time points, obtain rat whole blood via tailvain bleeding in Multivette 600 μl EDTA blood collection tubes(cat#151671100PK100, Sarstedt Inc) and use for ex vivo JAK1 and JAK2assay. Aliquot 100 ul of blood from each rat into a 96-well round bottomplate. Stimulate whole blood by recombinant IL-6 (00 ng/ml, andrecombinant mouse GM-CSF (cat#415-ML, lot#, R&D) for 12 min at rt. Aftercytokine stimulation, add whole blood into Lyse/fix (cat#558049, lot#,BD) in minitube rack; mix well 5×. Incubate 10 min at rt. Spin minituberack at 600 g for 4 min. Aspirate with 12-channel manifold. Transfercontents of minitube rack to 96 well round-bottom plates. Spin down thecells at 3000 rpm for 1 min and discard the supernatant. Mix the cellsin the well with 100 ul ice-cold MeOH and incubated on ice for 30 min.Add 150 ul PBS+2% FCS into each well and spin down at 3000 rpm, 2 min.Wash cells with 2× of 250 ul PBS+2% FCS. For cell surface andintracellular staining, mix all antibodies and add into each well andincubate 1 hr at rt in dark. The antibodies used for staining are asfollowing: pSTAT3, Alexa Fluor 647 (cat#4324s, lot, Cell Signaling);pSTAT5, Alexa Fluor 488 (cat#3939s, lot#, Cell Signaling), anti-rat CD4,V450 (cat#561579, lot#. BD); anti-rat CD11b, Percp eFluor710(cat#12-0110-82, lot#, eBioscience) After staining cells with Abs, washthe plates twice with PBS+2% FCS and finally re-suspend in the same 150ul of solution. Assess cell viability by Viability Dye 780(cat#65-0865-14, lot#, eBioscience). Perform the cytometry assay usingFORTESSA.

Following a protocol essentially as described above, the compounds ofExamples 4, and 6 to 10 and were tested, and the data is listed in Table6.

TABLE 6 Rat whole blood ex vivo JAK1 and JAK2 activity (% inhibition at30 mpk compared with vehicle treatment as 100% inhibition) JAK1 JAK2JAK1 JAK2 inhibition inhibition inhibition inhibition Example 2 hr post2 hr post 7 hr post 7 hr post No. dosing (%) dosing (%) dosing (%)dosing (%) 4 72.0 22.9 22.3 20.1 6 83.5 17.7 75.4 17.4 7 70.7 10.7 61.03.40

This data support the activity of the compounds of the Examples and thatthey are more potent for JAK1 over JAK2 in rats in vivo.

Rat Collagen-Induced Arthritis (CIA) Model

This protocol uses Lewis rats (weight 150-175 grams) from Charles River.On day 0, anesthetize rats with Isoflurane. On day 1, immunizeintradermally with collagen emulsion in two sites on the lower lumbarregion, above the base of the tail. Dose volume is a minimum of 0.4 mLper injection site. On day 8, anesthetize rats with Isoflurane andimmunize intradermally with collagen emulsion in two sites on the lowerlumbar region, above the base of the tail. Enroll rats into treatmentgroups on day 12, based on inflammation (redness and/or swelling) intheir hind paws. Randomize animals for Treatment Phase based on anklemeasurement values and body weight using block randomization allocationtool. Record ankle swelling on days 1, 8, and 11 and then three timesper week following enrollment up to and including the day of necropsy.Dose compounds orally once a day starting on day 12 (afterrandomization) up to day 25. The compounds of Examples 6 and 7 wereevaluated in the protocol essentially as described above. The resultsare listed in Table 7 below.

TABLE 7 Rat paw swelling inhibition (% inhibition compared with naïverat as 100% inhibition) Example % inhibition % inhibition % inhibitionNo. at 30 mpk at 10 mpk at 3 mpk 6 79 47 12 7 73 69 0

The data in Table 7 demonstrate that the compounds of Examples 6 and 7exhibit a dose responsive inhibition of paw swelling in rats, and lendsupport that the compounds of the Examples can be efficacious in thetreatment of arthritis.

Rat Adjuvant-Induced Arthritis (AIA) Model

The effects of compounds on polyarthritis inflammation and ankle jointbone erosion can be evaluated in a rat adjuvant-induced arthritis (AIA)model. Use Male Lewis rats with a mean body weight of 185 g for thestudy. Induce arthritis by intra-dermal injection located at the base ofthe tail with 100 μL of adjuvant suspended immunization emulsion oil.Randomize animals based on the mean paw thickness and body weight on day10 into study groups with 8 rats in each group. Prepare compounds in 1%HEC/0.25% P80/0.05% AF in purified water and dose daily via oral gavagestarting from day 11 post immunization for 14 days. Quantitate pawthickness with the caliper measurement on both ankles. Assess groupdifferences using a one-way ANOVA followed by Dunnett's post-test formultiple comparisons against vehicle controls. The compound of Example10 are evaluated in the protocol essentially as described above. Theresults are listed in Table 8 below.

TABLE 8 Paw swelling and bone mineral density (BMD) loss inhibition (%inhibition compared, with naïve rat as 100% inhibition) in rat AIA modelExample % inhibition of % inhibition of BMD No. 10 dose paw swellingloss in paw  3 mpk 26 39 10 mpk 63 81 30 mpk 73 84

The data in Table 8 demonstrate that the compound of Example 10 exhibita dose responsive inhibition of paw swelling in rats, and lend supportthat the compound of the Example can be efficacious in the treatment ofarthritis.

1. A compound of the formula, or a pharmaceutically acceptable saltthereof

wherein R is selected from: H, —C₁₋₃ alkyl, —CH₂CH(OH)CH₃, —C₂₋₃alkyl-O—CH₃,

R1 is selected from: H, —CH₃, and —OCH₃; R2 is —CHF₂ or —CF₃; R3 is H or—CH₃; provided when R2 is —CF₃ and R3 is H, either R or R1 can be —CH₃,but not both.
 2. A compound according to claim 1 of the formula, or apharmaceutically acceptable salt thereof,

wherein: R is selected from: H, —C₁₋₃ alkyl, —CH₂CH(OH)CH₃, —C₂₋₃alkyl-O—CH₃,

R1 is selected from: is selected from: H, —CH₃, and, —OCH₃; R2 is —CHF₂or —CF₃; and R3 is H or —CH₃; provided when R2 is —CF₃, and R3 is —CH₃,either R or R1 can be —CH₃, but not both.
 3. A compound according toclaim 2 wherein R is selected from: —CH₃, —CH₂CH₃, and

or a pharmaceutically acceptable salt thereof.
 4. A compound accordingto claim 3 wherein R is —CH₃, or —CH₂CH₃, or a pharmaceuticallyacceptable salt thereof.
 5. A compound according to claim 3 wherein R is

or a pharmaceutically acceptable salt thereof.
 6. A compound accordingto claim 1 wherein R1 is selected from: H, —CH₃, and —OCH₃, or apharmaceutically acceptable salt thereof.
 7. A compound according toclaim 6 wherein R2 is —CF₃, or a pharmaceutically acceptable saltthereof.
 8. A compound according to claim 7 wherein R3 is —CH₃, or apharmaceutically acceptable salt thereof.
 9. A compound according toclaim 1 which is

or a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 1 which is

or a pharmaceutically acceptable salt thereof.
 11. A compound accordingto claim 1 which is

or a pharmaceutically acceptable salt thereof.
 12. A compound accordingto claim 1 which is

or a pharmaceutically acceptable salt thereof.
 13. A compound which is(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate.
 14. A compound accordingto claim 12 which is(2R)-1,1,1-Trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-olin crystalline form characterized by an X-ray powder diffraction patternobtained from a CuKα source (λ=1.54056 Å), which comprises peaks at: a)15.5, 18.1, 18.3, 20.5, and 22.9+/−0.2° in 2 theta, or b) 13.2, 15.5,18.1, 18.3, 18.5, 20.5, 22.9, and 23.6, 23.7, +/−0.2° in 2 theta, or c)13.2, 15.5, 18.1, 18.3, 18.5, 19.0, 20.5, 22.9, 23.6, 23.6, 23.7, 24.7,and 26.5+/−0.2° in 2 theta.
 15. A compound according to claim 13 whichis(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate in crystalline formcharacterized by an X-ray powder diffraction pattern obtained from aCuKα source (λ=1.54056 Å), which comprises peaks at: a) 18.6, 19.1,21.0, and 22.4+/−0.2° in 2 theta, or b) 7.4, 11.0, 18.6, 19.1, 21.0,21.9, 22.4, and 26.2+/−0.2° in 2 theta or c) 7.4, 11.0, 12.7, 16.8,18.6, 19.1, 21.0, 21.9, 22.4, and 26.2, +/−0.2° in 2 theta.
 16. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier, diluent or excipient.
 17. Apharmaceutical composition comprising greater than 80% w/w of a compoundwhich is(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate in crystalline form.
 18. Apharmaceutical composition comprising greater than 90% w/w of a compoundwhich is(2R)-1,1,1-trifluoro-3-({cis-4-[(1-methyl-4-{[1-(pyridin-2-yl)-1H-pyrazol-3-yl]amino}-1H-benzimidazol-6-yl)oxy]cyclohexyl}amino)propan-2-ol2-hydroxypropane-1,2,3-tricarboxylate hydrate in crystalline form.
 19. Amethod of treating a patient in need of treatment for arthritis whereinthe method comprises administering to the patient an effective amount ofa pharmaceutical composition according to claim
 16. 20. A method oftreating a patient in need of treatment for arthritis wherein the methodcomprises administering to the patient an effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 21.(canceled)
 22. (canceled)
 23. (canceled)
 24. The compound according toclaim 12 which is:


25. A method of treating a patient in need of treatment for ulcerativecolitis wherein the method comprises administering to the patient aneffective amount of a compound according to claim 12, or apharmaceutically acceptable salt thereof.
 26. A method of treating apatient in need of treatment for Crohn's disease wherein the methodcomprises administering to the patient an effective amount of a compoundaccording to claim 12, or a pharmaceutically acceptable salt thereof.27. A method of treating a patient in need of treatment for systemiclupus erythrematosus wherein the method comprises administering to thepatient an effective amount of a compound according to claim 12, or apharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition comprising a compound according to claim 12 and apharmaceutically acceptable carrier, diluent or excipient.